The present invention relates to methods for monitoring particle size during chemical operations. Particle size monitoring is employed in a wide variety of pharmaceutical and chemical development and manufacturing programs.
The methods known in the art for determining particle size are laborious, time consuming and potentially inaccurate. In general, samples are obtained from the processing equipment, transported to another building/facility and analyzed. Dilutions of approximately 1000 fold are first necessary, and then the samples are “particle sized” such as by laser light scattering with a Coulter LS230 or a Horiba LA-910 commercial particle size instrument. This instrument reports a mean particle size and D90 values (a size of which 90% of the particles are less than this value). The use of the Coulter LS230 requires sampling from the process stream, delivery of sample to an analytical laboratory, significant dilution of the sample and then approximately an additional 30 minutes to generate results. The overall process can take up to an hour, raises concerns about the integrity of the sample generated, and does not provide real time feedback for process monitoring or control. The imitations of methods known in the art include difficulties of off line monitoring, laborious process, physical distance between process and analytic laboratory, non-homogeneities in samples, dilution effects, unrepresentative sample collection, changes in the sample over time and the lag time in processing while waiting for the analysis.
The present invention overcomes the limitations of methods known in the art such as those which employ the Coulter LS230 instrument (or similar methodology). Moreover, in contrast to previously known methods, the present invention results in improved sensitivity to changes in the process near the end of the process cycle. The ultimate utilization of this monitoring scheme can allow the operator to terminate the process operation when the particles have reached the desired size distribution as soon as that condition is reached. The improved efficiency will allow more effective use of processing time, resulting in reductions of manufacturing cycle times to be realized over the manufacturing life cycle of any chemical product that is prepared utilizing such technology.